Above, bones stained with osmium. Left: bone fat decreased due to exercise. Right: bones of mice on high dose of rosiglitazone. Far right image shows decrease in bone fat due to exercise. (Credit: UNC)

A new study shows how some diabetes drugs substantially increase the amount of marrow fat in bones, which raises the risk of bone fractures.

The study, published in the journal Endocrinology, also shows that exercise can decrease the volume of bone fat caused by high doses of the diabetes drug rosiglitazone, which is sold under the brand name Avandia.

“These drugs aren’t first or second-line choices of treatment for type 2 diabetes, but some patients do take them,” says first author Maya Styner, assistant professor of medicine at the UNC School of Medicine. “And we know there are drugs in development that target the same cellular pathways as rosiglitazone does.

“We think doctors and patients need to better understand the relationship between diabetes, certain drugs, and the often dramatic effect on bone health.”

According to Styner’s study, rosiglitazone affects bone fat by enhancing a critical transcription factor called PPAR—peroxisome proliferator-activated receptor—which regulates the expression of specific genes in the nuclei of cells.

Essentially, rosiglitazone takes glucose out of blood to lower blood sugar and treat diabetes. But that glucose is then packaged into lipid droplets—fat. Other researchers showed that some of that fat is stored in tissue, such as belly fat.

Natural runners

In the research, Styner’s team added a running wheel to the cages of mice, which are natural runners. At night, they’d run several miles on the wheel. Styner’s team then measured the effects of running. Even on a high dose of a power drug, such as rosiglitazone, the mice that exercised showed a significant decrease in bone fat.

Styner says her findings are not yet directly relatable to human activity. For humans, running isn’t nearly as natural. But she says she would still advise patients at risk of declining bone health to find an exercise that suits them; the default would be taking very long walks.

Styner’s latest research shows that the drug also causes fat to be stored inside bone.

“First, we were surprised by the massive amount of bone fat caused by rosiglitazone,” Styner says. “The images were just stunning. Also, the drug is so powerful and we used such a high dose that we didn’t think exercise would decrease the fat depot much, if at all. But exercise did decrease the volume of bone fat by about 10 percent, which was similar to the decrease we reported seeing in mice that were not given the drug but were instead fed a high-fat diet.”

Diabetes drugs

Styner says that many of her patients have been surprised to learn that some diabetes drugs can adversely affect bone health. She also says that diabetes itself can harm bones.

Avandia fell out of favor about a decade ago because of heart-related side effects. Physicians can still prescribe the drug, but it isn’t as popular as it once was. Its cousin pioglitazone is also still available and has been shown to cause fewer heart-related side effects, Styner says, but it also isn’t used as a first or second-line drug to treat diabetes.

Yet, other drugs under development that could be close to FDA-approval lower blood sugar by enhancing the PPAR pathway. These drugs are referred to as fibroblast growth factor-21 agonists. “Early reports show that the same bone concerns are popping up with these new drugs,” Styner says. “Doctors and patients need to be aware of this.”

Is bone fat just energy storage?

Bone fat, in general, isn’t nearly as well understood as other fat depots. “Our field is just beginning to investigate bone fat and its implications for patients,” Styner says. But she says that more bone fat means less actual bone, which increases the risk of bone fractures.

All of us have fat in our bones—it’s just a matter of how much. Styner says that the same kind of stem cell in our marrow creates bone cells and fat cells. Previously, Styner used a new osmium staining technique to visualize that a high-fat diet increases the fat depots in the bones of mice, just as a high-fat diet increases belly fat.

There are still differing theories for how bone fat increases due to a high-fat diet and how exercise lowers it. Styner says exercise might trigger marrow stem cells to create more bone cells instead of fat cells. Or perhaps exercise causes the body to access bone fat as fuel.

“It could be that bone fat is just another depot, a good energy store that allows bone cells to do what they need to do so bones become stronger,” Styner says.

Styner hopes to work with exercise scientists to use advanced MRI technologies to visualize the effects of exercise on human bone health.